Remediating Desmoplasia with EGFR-Targeted Photoactivable Multi-Inhibitor Liposomes Doubles Overall Survival in
Girgis Obaid1, Shazia Bano1, Hanna Thomsen1
1Department of Dermatology, Massachusetts General Hospital and Harvard Medical School, Boston, MA, 02114, USA.
Abstract:
Desmoplasia is characteristic of pancreatic ductal adenocarcinoma (PDAC), which exhibits 5-year survival rates of 3%. Desmoplasia presents physical and biochemical barriers that contribute to treatment resistance, yet depleting the stroma alone is unsuccessful and even detrimental to patient outcomes. This study is the first demonstration of targeted photoactivable multi-inhibitor liposomes (TPMILs) that induce both photodynamic and chemotherapeutic tumor insult, while simultaneously remediating desmoplasia in orthotopic PDAC. TPMILs targeted with cetuximab (anti-EGFR mAb) contain lipidated benzoporphyrin derivative (BPD-PC) photosensitizer and irinotecan. The desmoplastic tumors comprise human PDAC cells and patient-derived cancer-associated fibroblasts. Upon photoactivation, the TPMILs induce 90% tumor growth inhibition at only 8.1% of the patient equivalent dose of nanoliposomal irinotecan (nal-IRI). Without EGFR targeting, PMIL photoactivation is ineffective. TPMIL photoactivation is also sixfold more effective at inhibiting tumor growth than a cocktail of Visudyne-photodynamic therapy (PDT) and nal-IRI, and also doubles survival and extends progression-free survival by greater than fivefold. Second harmonic generation imaging reveals that TPMIL photoactivation reduces collagen density by >90% and increases collagen nonalignment by >103 -fold. Collagen nonalignment correlates with a reduction in tumor burden and survival. This single-construct phototoxic, chemotherapeutic, and desmoplasia-remediating regimen offers unprecedented opportunities to substantially extend survival in patients with otherwise dismal prognoses.
Insights
Targeted photoactivable multi-inhibitor liposomes (TPMILs) offer a novel approach for pancreatic ductal adenocarcinoma (PDAC) treatment. This therapy combines photodynamic and chemotherapeutic effects while reducing tumor desmoplasia, significantly improving survival rates.
Area of Science:
- Oncology
- Nanomedicine
- Biochemistry
Background:
- Pancreatic ductal adenocarcinoma (PDAC) is characterized by desmoplasia, a dense tumor stroma that creates physical and biochemical barriers, leading to poor treatment response and a 5-year survival rate of only 3%.
- Current therapeutic strategies that target only the stroma have proven unsuccessful and can be detrimental to patient outcomes.
Purpose of the Study:
- To develop and evaluate targeted photoactivable multi-inhibitor liposomes (TPMILs) as a novel therapeutic agent for PDAC.
- To assess the efficacy of TPMILs in inducing combined photodynamic and chemotherapeutic effects while simultaneously remediating tumor desmoplasia.
Main Methods:
- TPMILs were engineered with cetuximab (anti-EGFR mAb) for targeted delivery, containing a lipidated benzoporphyrin derivative (BPD-PC) photosensitizer and irinotecan.
- The study utilized orthotopic PDAC models comprising human PDAC cells and patient-derived cancer-associated fibroblasts.
- Efficacy was evaluated through tumor growth inhibition, survival studies, progression-free survival analysis, and second harmonic generation imaging to assess collagen density and nonalignment.
Main Results:
- Photoactivated TPMILs demonstrated significant tumor growth inhibition (90%) at a fraction of the standard dose of nanoliposomal irinotecan (nal-IRI).
- EGFR targeting was crucial for TPMIL efficacy; without it, photoactivation was ineffective.
- TPMIL photoactivation was sixfold more effective than a combination of Visudyne-photodynamic therapy (PDT) and nal-IRI, doubling survival and extending progression-free survival by over fivefold.
- TPMIL photoactivation drastically reduced collagen density (>90%) and increased collagen nonalignment (>103-fold), which correlated with reduced tumor burden and improved survival.
Conclusions:
- TPMILs represent a first-in-class therapeutic construct capable of delivering combined phototoxic and chemotherapeutic insults while remodeling the tumor microenvironment.
- This multi-modal approach offers a promising strategy to overcome treatment resistance in PDAC and significantly extend survival in patients with poor prognoses.
